The HIV-1 envelope (env) glycoprotein is a structurally complex integral membrane protein that targets the virus to CD4 positive cells and mediates the fusion between the viral envelope and the cellular membrane. This glycoprotein also harbors antigenic determinants that are recognized by neutralizing antibodies.
The two recognized categories of antibodies that are capable of neutralizing HIV-1 infection include: those that recognize determinants in the V3 loop of gp120 and those that block the gp120-CD4 interaction by binding to conserved regions of gp120. Antibodies directed against the V3 loop generally recognize epitopes formed by a short continuous sequence and are usually referred to as conformation-independent. These conformation-independent antibodies can be elicited by immunization with either peptides or denatured env protein subunits. Extensive antigenic variation in the V3 domain of the env protein restricts the neutralizing activity of anti-V3 loop antibodies to closely related strains of HIV-1. Hence, antibodies capable of neutralizing infection by one strain of HIV-1 may not effectively neutralize infection by a different strain of HIV-1.
In contrast, antibodies to epitopes that are sensitive to the conformation of the protein are typically more broadly neutralizing. Antibodies to these conformation-sensitive epitopes are referred to herein as "conformation-dependent" antibodies. Conformation-dependent antibodies that block CD4 binding, for example, recognize conserved, discontinuous, conformational epitopes in gp120. These antibodies are broadly neutralizing and have been shown to comprise a significant fraction of the total neutralization activity present in HIV-1 infected human sera. In addition, there is evidence that neutralizing antibodies may also be directed against conformationally-dependent epitopes on gp120 (Steimer et al., Science, 254:105 (1991)).
Newly synthesized gp160 monomers noncovalently associate to form higher order oligomeric structures. The association of two env monomers to form a dimer is the most elemental such structure. A larger structure that is believed to be composed of a dimer of dimers, or four monomers, can also form. The ectodomain of gp41 is required for efficient oligomerization of dimers and tetramers (Earl et al., Proc. Natl. Acad. Sci. USA 87:648 (1990); Earl and Moss, AIDS Res. 9:589-594 (1993)).
Given its antigenic nature, the use of recombinant gp160 or derivatives thereof as immunogens represents an attractive vaccine strategy. However, the attempts that have been made to date in this regard have all suffered one or another deficiency. To the extent that humoral immune responses against various gp160 immunogens have been analyzed, none satisfactorily stimulates the broadly neutralizing antibodies that would be required of an effective HIV-1 vaccine. Hence, there remains a need for a vaccine composition that can stimulate the production of broadly neutralizing antibodies against various strains of HIV-1.